Combination of Bedaquiline plus Delaminid within a treatment regimen for Pre-XDR TB; experience of a tolerable regimen and acceptable safety profile for the first time in Scotland

Introduction: A 29 year old female of Pakistani origin was diagnosed with MDR-TB affecting cervical nodes, with pulmonary and laryngeal disease demonstrated on CT. Genotypic (and subsequent phenotypic) testing demonstrated pre-XDR resistance pattern with Izoniazid, Rifampicin, Ethambutol & Fluroquinolone resistance. Methods: Following commencement of induction regimen with Amikacin, Cycloserine, Prothionamide, Pyrazinamide, Linezolid and Clofazimine, borderline ototoxicity developed after 6 months, necessitating a switch from Amikacin to Bedaquiline. After around 10 months, Linezolid and Cycloserine were discontinued sequentially due to progressively debilitating peripheral neuropathy, PAS was subsequently added to the regimen which was poorly tolerated. PAS was substituted for Delaminid (used with Bedaquiline, Clofazimine and Pyrazinamide) despite concerns regarding potential cumulative QTc prolongation effects. Patient was counselled regarding risk of cardiac arrhythmias; fortnightly ECG monitoring was agreed to for three months, then monthly thereafter. Manual calculations of QTc were performed using Fredericia formula. Results: QTc rose maximally to 491 ms (89ms greater than baseline). Clinical and radiological monitoring demonstrated favourable improvement in condition. No further adverse events or toxicities were reported. The patient continues to tolerate the regimen well with no components of the regimen requiring discontinuation. Dicussion: Bedaquiline and Delamanid are rarely used together in combination due to risk of QTc prolongation; in this clinical case they were used with no concerns being raised regarding safety or tolerability. Our experience corresponds with the international data produced by Ferlazzo et al. Whilst further large volume safety data is awaited, compassionate use of alternative drug regimens within strict monitoring guidelines should be considered.